Adolescent depression is a major public health problem that frequently recurs in the patient's life with significant costs to the adolescent and society. Presently, our understanding of the underlying neural substrates of adolescent depression is very limited. The number of pediatric functional neuroimaging studies is extremely sparse. The few functional magnetic resonance imaging (fMRI) studies of the amygdala in pediatric depression have reported opposite results. There are no published fMRI studies examining the subgenual anterior cingulate or dorsal lateral prefrontal cortex in depressed adolescents relative to matched, healthy adolescents except for the recent publication by the Principal Investigator (Dr. Yang). Furthermore, there are no published functional neuroimaging studies in depressed adolescents examining possible brain regions that might be predictors of future clinical response to treatment. Description: This proposal is both a cross-sectional and longitudinal follow-up study. In this application, we plan to: (1) recruit 64adolescents with major depressive disorder (MDD) and 64 healthy, control adolescents; and (2) follow the depressed adolescents longitudinally over 6 months after the initial assessment. MDD and healthy adolescents ages 13 to 17 years will participate in this study. Both genders and all ethnicities will be included. Recruitment will be through several major sources using the same approach as established in 5K23MH070791. Similarly, using the same approach established in 5K23MH070791, all adolescents will be carefully screened and undergo a series of interviews, questionnaires, and assessments to obtain information pertinent to this study. Adolescents will be scanned using fMRI tasks that activate the adolescent amygdala, dorsal lateral prefrontal cortices, and subgenual anterior cingulate cortex. A single fMRI scan will occur at baseline. Clinical assessments will occur at baseline, 3 months, and 6 months. The 6-month clinical assessment will be the primary time point of interest for the longitudinal study. The Children's Depression Rating Scale-Revised (CDRS-R) will be the primary clinical outcome measure. The Beck Depression Inventory II and Children's Global Assessment Scale will be the secondary clinical outcome measures. Aims: Aims of the current proposal are to: (1) contrast brain activation in the amygdala, dorsal lateral prefrontal cortices (DLPFC), and subgenual anterior cingulate cortex (sgACC) using fMRI between adolescents with MDD and matched healthy controls, and (2) evaluate the relationship between fMRI activation in the amygdala, DLPFC, and sgACC at baseline and the future clinical response to treatment in adolescents with MDD. Accomplishing these aims will advance the neurobiology of adolescent depression by: (1) contributing to an overall understanding and model of adolescent depression that can be used to develop clinically relevant tools, and (2) taking the necessary first steps towards the translation of basic functional neuroimaging findings into a useful clinical tool that can predict future treatment response in depressed adolescents. PUBLIC HEALTH RELEVANCE: Depression is a major public health problem that frequently recurs in the patient's life with significant costs to the adolescent and society. This functional magnetic resonance imaging study will advance the understanding and treatment of adolescent depression by: (1) further elucidating the underlying network of cortical and subcortical brain structures that are affected in adolescent depression by performing a cross- sectional study in depressed and healthy adolescents, and (2) taking the initial steps towards utilizing the knowledge gained from a deeper understanding of which brain structures are affected in depressed adolescents to aid the development of a clinically relevant fMRI tool that has the potential to predict future treatment response in depressed adolescents.